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Robust Angiogenesis and Arteriogenesis in the Skin of Diabetic Mice by Transient Delivery of Engineered VEGF and PDGF-BB Proteins in Fibrin Hydrogels

Non-healing ulcers are a serious complication of diabetes mellitus and a major unmet medical need. A major cause for the lack of healing is the impairment of spontaneous vascularization in the skin, despite mostly normal blood flow in deeper large vessels. Therefore, pro-angiogenic treatments are ne...

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Autores principales: Certelli, Alessandro, Valente, Paolo, Uccelli, Andrea, Grosso, Andrea, Di Maggio, Nunzia, D’Amico, Rosalinda, Briquez, Priscilla S., Hubbell, Jeffrey A., Wolff, Thomas, Gürke, Lorenz, Mujagic, Edin, Gianni-Barrera, Roberto, Banfi, Andrea
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8281302/
https://www.ncbi.nlm.nih.gov/pubmed/34277588
http://dx.doi.org/10.3389/fbioe.2021.688467
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author Certelli, Alessandro
Valente, Paolo
Uccelli, Andrea
Grosso, Andrea
Di Maggio, Nunzia
D’Amico, Rosalinda
Briquez, Priscilla S.
Hubbell, Jeffrey A.
Wolff, Thomas
Gürke, Lorenz
Mujagic, Edin
Gianni-Barrera, Roberto
Banfi, Andrea
author_facet Certelli, Alessandro
Valente, Paolo
Uccelli, Andrea
Grosso, Andrea
Di Maggio, Nunzia
D’Amico, Rosalinda
Briquez, Priscilla S.
Hubbell, Jeffrey A.
Wolff, Thomas
Gürke, Lorenz
Mujagic, Edin
Gianni-Barrera, Roberto
Banfi, Andrea
author_sort Certelli, Alessandro
collection PubMed
description Non-healing ulcers are a serious complication of diabetes mellitus and a major unmet medical need. A major cause for the lack of healing is the impairment of spontaneous vascularization in the skin, despite mostly normal blood flow in deeper large vessels. Therefore, pro-angiogenic treatments are needed to increase therapeutic perfusion by recruiting new arterial connections (therapeutic arteriogenesis). Vascular endothelial growth factor (VEGF) is the master regulator of angiogenesis in physiology and disease, but exploitation of its therapeutic potential requires careful control of its dose distribution in tissue. Co-delivery of platelet derived growth factor-BB (PDGF-BB) has been shown to expand the therapeutic window of VEGF and also improve associated arteriogenesis. We used a highly controlled protein delivery system, based on a clinically applicable fibrin-based platform, to investigate the angiogenic and arteriogenic potential of engineered versions (TG-) of VEGF and PDGF-BB proteins in the skin of diabetic and obese db/db mice. Intradermal delivery of therapeutically relevant doses of TG-VEGF and TG-PDGF-BB induced robust growth of new microvascular networks with similar efficacy as in normal littermate control mice. Further, TG-PDGF-BB prevented the formation of aberrant vascular enlargements by high TG-VEGF levels. As fibrin was degraded after the first week, the induced angiogenesis mostly regressed by 4 weeks, but it promoted effective arteriogenesis in the dermal layer. Therefore, controlled co-delivery of TG-VEGF and TG-PDGF-BB recombinant proteins is effective to induce angiogenesis and arteriogenesis in diabetic mouse skin and should be further investigated to promote diabetic wound healing.
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spelling pubmed-82813022021-07-16 Robust Angiogenesis and Arteriogenesis in the Skin of Diabetic Mice by Transient Delivery of Engineered VEGF and PDGF-BB Proteins in Fibrin Hydrogels Certelli, Alessandro Valente, Paolo Uccelli, Andrea Grosso, Andrea Di Maggio, Nunzia D’Amico, Rosalinda Briquez, Priscilla S. Hubbell, Jeffrey A. Wolff, Thomas Gürke, Lorenz Mujagic, Edin Gianni-Barrera, Roberto Banfi, Andrea Front Bioeng Biotechnol Bioengineering and Biotechnology Non-healing ulcers are a serious complication of diabetes mellitus and a major unmet medical need. A major cause for the lack of healing is the impairment of spontaneous vascularization in the skin, despite mostly normal blood flow in deeper large vessels. Therefore, pro-angiogenic treatments are needed to increase therapeutic perfusion by recruiting new arterial connections (therapeutic arteriogenesis). Vascular endothelial growth factor (VEGF) is the master regulator of angiogenesis in physiology and disease, but exploitation of its therapeutic potential requires careful control of its dose distribution in tissue. Co-delivery of platelet derived growth factor-BB (PDGF-BB) has been shown to expand the therapeutic window of VEGF and also improve associated arteriogenesis. We used a highly controlled protein delivery system, based on a clinically applicable fibrin-based platform, to investigate the angiogenic and arteriogenic potential of engineered versions (TG-) of VEGF and PDGF-BB proteins in the skin of diabetic and obese db/db mice. Intradermal delivery of therapeutically relevant doses of TG-VEGF and TG-PDGF-BB induced robust growth of new microvascular networks with similar efficacy as in normal littermate control mice. Further, TG-PDGF-BB prevented the formation of aberrant vascular enlargements by high TG-VEGF levels. As fibrin was degraded after the first week, the induced angiogenesis mostly regressed by 4 weeks, but it promoted effective arteriogenesis in the dermal layer. Therefore, controlled co-delivery of TG-VEGF and TG-PDGF-BB recombinant proteins is effective to induce angiogenesis and arteriogenesis in diabetic mouse skin and should be further investigated to promote diabetic wound healing. Frontiers Media S.A. 2021-07-01 /pmc/articles/PMC8281302/ /pubmed/34277588 http://dx.doi.org/10.3389/fbioe.2021.688467 Text en Copyright © 2021 Certelli, Valente, Uccelli, Grosso, Di Maggio, D’Amico, Briquez, Hubbell, Wolff, Gürke, Mujagic, Gianni-Barrera and Banfi. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Bioengineering and Biotechnology
Certelli, Alessandro
Valente, Paolo
Uccelli, Andrea
Grosso, Andrea
Di Maggio, Nunzia
D’Amico, Rosalinda
Briquez, Priscilla S.
Hubbell, Jeffrey A.
Wolff, Thomas
Gürke, Lorenz
Mujagic, Edin
Gianni-Barrera, Roberto
Banfi, Andrea
Robust Angiogenesis and Arteriogenesis in the Skin of Diabetic Mice by Transient Delivery of Engineered VEGF and PDGF-BB Proteins in Fibrin Hydrogels
title Robust Angiogenesis and Arteriogenesis in the Skin of Diabetic Mice by Transient Delivery of Engineered VEGF and PDGF-BB Proteins in Fibrin Hydrogels
title_full Robust Angiogenesis and Arteriogenesis in the Skin of Diabetic Mice by Transient Delivery of Engineered VEGF and PDGF-BB Proteins in Fibrin Hydrogels
title_fullStr Robust Angiogenesis and Arteriogenesis in the Skin of Diabetic Mice by Transient Delivery of Engineered VEGF and PDGF-BB Proteins in Fibrin Hydrogels
title_full_unstemmed Robust Angiogenesis and Arteriogenesis in the Skin of Diabetic Mice by Transient Delivery of Engineered VEGF and PDGF-BB Proteins in Fibrin Hydrogels
title_short Robust Angiogenesis and Arteriogenesis in the Skin of Diabetic Mice by Transient Delivery of Engineered VEGF and PDGF-BB Proteins in Fibrin Hydrogels
title_sort robust angiogenesis and arteriogenesis in the skin of diabetic mice by transient delivery of engineered vegf and pdgf-bb proteins in fibrin hydrogels
topic Bioengineering and Biotechnology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8281302/
https://www.ncbi.nlm.nih.gov/pubmed/34277588
http://dx.doi.org/10.3389/fbioe.2021.688467
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